The Mucosal Immune Response
The vast majority of agents of infection in vertebrates enter the host across a mucosal surface, including generally the mucosa of the alimentary canal (including oral mucosa), the respiratory tract (including olfactory and conjunctival mucosa), the mammary glands, and the genitourinary tract. The common mucosal immune system, by way of the secretory immunoglobulin response, provides a first line of resistance to infection across mucosal surfaces in vertebrates (J. Mestecky (1987). J. Clin. Immunol. 7:265-75).
The secretory immune response entails, among other events, clonal proliferation of antigen-specific B cells and progressive isotype switching by the B cell progeny to all subclasses of IgG- and IgA-secreting cells. Antigens such as microorganisms, proteins, polysaccharides, etc., that are encountered at a mucosal site can elicit local production of antibodies into the secretions that bathe the mucosal surface at the site, as well as other mucosal sites.
It is well established that in many species, including humans, the daily combined production of secretory and circulating IgA exceeds that of other immunoglobulin isotypes. Secretory IgA as well as IgM and all subclasses of IgG have been found in virtually all external secretions, including tears, saliva, colostrum and milk, and in the mucous secretions of the respiratory, intestinal and genitourinary tracts. In most species, the systemic and secretory production of immunoglobulins maintain a considerable degree of independence. For example, in humans, the majority of serum IgA is produced in the bone marrow, and is not found in secretions. The vast majority of secretory IgA is produced by plasma cells distributed in the lamina propria of the common mucosal epithelia of the body. Furthermore, locally produced secretory IgA does not contribute significantly to the circulating pool of IgA. The IgA of secreted body fluids is known to be assembled within IgA-producing cells in a polymeric form before selective transport to external surfaces. The IgA present in plasma and in cerebrospinal fluid is predominantly monomeric in structure (i.e., approximately 7-8S), while the majority of the secreted forms of IgA are dimeric.
The protective role of secretory IgA has been well demonstrated in both clinical and experimental systems. As a potent mechanism for the prevention of infectious diseases and for the inhibition of allergic reactions at mucosal surfaces, secreted IgA neutralizes biologically active antigens, prevents uptake of antigens from the intestinal tract, inhibits adherence of bacteria to epithelial surfaces and enhances the antibacterial effects of the innate defense system (see J. Mestecky (1987), supra). Numerous studies have determined that the mucosa are endowed with a specialized lymphoid tissue which induces and regulates the immune response of external secretions. The gut-associated lymphoreticular tissue ("GALT") includes both the Peyer's Patches, which are distinct lymphoid nodules along the small intestines, and the solitary lymphoid nodules. Lymphoid nodules bear a characteristic histologic organization with an epithelium comprised of cuboidal epithelial cells and microfold cells ("M cells"). M cells possess numerous cytoplasmic vesicles and cytoplasmic extensions which surround the lymphoreticular cells in the underlying region, called the dome. It is thought that M cells serve as an antigen-sampling mechanism for the uptake of lumenal antigens and their intact transport across the epithelium. The dome area is rich in MHC class II.sup.+ cells (macrophages, dendritic cells and B cells), which should create a superb environment for the important function of antigen presentation. The dome also contains many T cells, the function of which is not well-defined. Underneath the dome are situated two follicle areas which represent B cell zones enriched in B cells that can become committed to IgA production. However, unlike germinal centers in other secondary lymphold tissue, B cell development and differentiation into plasma cells rarely occur in this tissue.
Once antigen penetrates the mucosal epithelial cells, antigen-presenting cell-dependent activation of paracortical T cells and germinal center B cells within the Peyer's Patches is observed. However, the inductive stimuli required for differentiation of IgA-committed B cells is deferred until B cells have migrated through efferent lymphatics into the mesenteric lymph nodes after departure from the Peyer's Patches. Ultimately, IgA-committed, antigen-sensitized B cells enter the circulation through the lymph to populate various exocrine glands and mucosal epithelia throughout the body. Under local influences which include information provided by helper T cells, by the antigen and other biochemical mediators, terminal differentiation into IgA-secreting plasma cells occurs.
The microenvironment of the Peyer's Patch, which favors development of IgA-committed B cells, has been a focal point of research on the mucosal immune system (J. Bienenstock et al. (1983). Fed. Proc. 42: 3215-17; J. Mestecky (1987), supra). The process of isotype-switching which commits Peyer's Patch B cells to IgA production is known to be under the regulation of T cells and specialized T cell effector function (J. Bienenstock et al. (1983), supra). A natural distribution in the pattern of cytokines made by T cells in distinct lymphoid compartments is emerging from recent work (R. Daynes et al. (1990) J. Exp. Med. 171: 979-96; B. Araneo et al. (1993). J, Inf. Diseases 171: 830-840). T cells residing in lymphold tissue that receives drainage from the skin (that is, from peripheral lymph nodes) produce high levels of IL-2 and IFN-.gamma. when activated. T cells isolated from lymphold tissue, including Peyer's Patch, that receive their primary drainage from mucosal surfaces (mucosal lymph nodes) produce a pattern of cytokines enriched in IL-4 and IL-5, but low in IL-2 and IFN-.gamma., following activation. The ability of cytokines to direct immunoglobulin class switching by activated B cells is a well-studied and well-accepted phenomenon. See, e.g., Finkelman et al. (1990). Ann, Rev. Immunol. 8: 303-34. In several cases, the molecular mechanism regulating immunoglobulin class-switching has been defined (Finkelman et al. (1990), supra). Investigations by Kiyono et al. (1984). Jour. Exp. Med. 159: 798-811, and H. Kawanishi et al. (1983). Jour. Exp. Med. 157: 433-50, indicate that Peyer's Patch T cells cause switching of IgM-bearing B cells to IgA-bearing B cells. These "switch" T cells do not facilitate class-switching of IgG-bearing B cells to IgA-bearing. Importantly, antigen-specific Peyer's Patch-derived T cell clones are able to mediate maturation and differentiation of IgA-bearing B cells into IgA-secreting cells. Kiyono et al., supra, concluded that growth and differentiation factors made by antigen-specific Peyer's Patch T cells is responsible for the selective enhancement of IgA at gut mucosal surfaces.
As a consequence of the major emphasis on the specialized function and lymphokine-producing potential of Peyer's Patch T cells in the initiation of the mucosal immune process, research in this important field has centered on the delivery of antigen across mucosal surfaces as a requirement for successful vaccination against infectious agents where mucosal immunity is essential. Research efforts, therefore, have been almost universally focused on the induction of mucosal immune responses by providing antigen to and stimulating cells in the local mucosa-draining lymphoid organs.